DESCRIPTION: To design biomaterials for applications such as tissue repair, cell delivery, or therapeutic delivery, the prevailing approach for dealing with the immune system has been to avoid it. However, as newer classes of biomaterials and combination products increasingly contain proteins, peptides, and cells, it is becoming challenging to avoid adaptive immune responses entirely. Having a way to shape, or polarize such responses into phenotypes that promote healing would greatly accelerate the clinical translation of these promising new technologies. However, design principles for accomplishing this are currently in their infancy, owing to a lack of biomaterials platforms that can be systematically adjusted to elicit various adaptive immune phenotypes, including Th2 versus Th1 polarization. In this project we will address these challenges by designing novel nanofibers and hydrogels from self-assembling peptides and proteins that have modular control over epitope content, the precise ratios of multiple T cell-polarizing cytokines, and their persistence in vivo. We will use these materials to test the central hypothesis that materials eliciting short-duration, non- inflammatory, Th2-polarized immune responses will promote a pro-healing environment surrounding the biomaterial. We have previously taken the first step in this work by designing novel self-adjuvanting peptide self-assemblies that are non-inflammatory and well tolerated in tissue defects. To polarize these materials towards Th2 or Th1 phenotypes, and to understand how polarization affects healing, we will develop a new self-assembling technology, ?-tail proteins. ?-tail proteins can be induced to self-assemble into nanofibers and gels containing precisely controlled amounts of multiple different proteins of choice. To polarize T cell responses and direct them specifically against the material, tail derivatives of T cell polarizing cytokines (IL-, IL-10, IFN, IL-2) will be co-assembled with defined T cell and B cell epitopes. To control persistence and degradation of the materials, we will develop hydrolytically susceptible self-assembling depsipeptides, with ester bonds at targeted locations in the amide backbone. Immune responses will be measured in mouse models using antibody isotyping, histology, ELISPOT, and adoptive transfer experiments. In full- thickness excisional dermal wounds, the materials will be systematically engineered to facilitate healing via the adaptive immune system, and the independent role of Th1/Th2 T cell polarization will be determined by depleting T cells at several time points during the healing process. This work will take advantage of an actively collaborating multidisciplinary team of investigators with expertise in biomaterials, immunology, Th1/Th2 polarization, and reconstructive surgery. The knowledge gained will not only provide critical new materials for tissue repair but also clarify design principles for eliciting productiv adaptive immune responses for next-generation devices containing proteins, peptides, and cells.